Artificial Extracorporeal Liver Support Research Articles

Hepatitis B Virus Reactivation in Gastrointestinal Stromal Tumor Patients Treated With Imatinib.

PurposeHepatitis B virus reactivation (HBVr) in patients with gastrointestinal stromal tumors (GISTs) have not been sufficiently characterized. This study aimed to review the possible mechanism of HBVr induced by imatinib and explore appropriate measures for patient management and monitoring.MethodsThe clinical data of GIST patients who experienced HBVr due to treatment with imatinib at Xiangya Hospital (Changsha, Hunan, China) were retrospectively analyzed. A literature review was also conducted.ResultsFive cases were analyzed, including 3 cases in this study. The average age of the patients was 61.8 y, with male preponderance (4 of 5 vs. 1 of 5). These patients received imatinib as adjuvant treatment (n=4) or as neoadjuvant treatment (n=1). Primary tumors were mostly located in the stomach (n=4) or rectum (n=1). High (n=3) or intermediate (n=1) recurrence risk was categorized using the postoperative pathological results (n=4). Imatinib was then started at 400 (n=4) or 200 mg (n=1) daily. Patients first reported abnormal liver function during the 2th (n=1),6th (n=3), or 10th (n=1) month of treatment with imatinib. Some patients (n=4) discontinued imatinib following HBVr; notably, 1 month after discontinuation, 1 patient experienced HBVr. Antivirals (entecavir n=4, tenofovir n=1), artificial extracorporeal liver support (n=1), and liver transplant (n=1) were effective approaches to treating HBVr. Most patients (n=3) showed favorable progress, 1 patient underwent treatment, and 1 patient died due to severe liver failure induced by HBVr.ConclusionsAlthough HBVr is a rare complication (6.12%), HBV screening should be conducted before starting treatment with imatinib in GIST patients. Prophylactic therapy for hepatitis B surface antigen positive patients, prompt antiviral treatment and cessation of imatinib are also necessary.

Artificial liver support in acute and acute-on-chronic liver failure.

Liver failure is a life-threatening condition, and an artificial liver is highly desirable to replace the failing liver-functions in the waiting time for liver regeneration to happen or until liver transplantation can be undertaken. This review focuses on the efficacy of using artificial extracorporeal liver support devices. Artificial liver support devices such as the molecular adsorbent recirculating system (MARS), fractionated plasma separation and adsorption, and therapeutic plasma exchange (TPE) are well tolerated. MARS and TPE improve systemic haemodynamics and the grade of hepatic encephalopathy. However, randomized, controlled trials of MARS and fractionated plasma separation and adsorption have failed to show improvement in survival in patients with acute liver failure (ALF) and patients with acute-on-chronic liver failure (ACLF). Only TPE improves survival in patients with ALF by ameliorate the release of ammonia, damage-associated molecular patterns and sB7 (CD80/86) from the necrotic liver. No randomized, controlled trials on survival in patients with ACLF using TPE have been done. Liver support systems such as MARS and TPE may temporarily improve systemic haemodynamics and the degree of encephalopathy. However, TPE is the only procedure that improves survival in patients with ALF. The role of TPE in ACLF remains unknown.

Emerging Role of Extracorporeal Support in Acute and Acute-on-Chronic Liver Failure: Recent Developments

Acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) are life-threatening illnesses requiring intensive care admission and potentially liver transplantation. Artificial extracorporeal liver support (ECLS) systems remove water-soluble and albumin-bound toxins to maintain normal serum chemistry, prevent further hepatic/organ system damage, and create an environment for potential hepatic regeneration/recovery (ALF) or bridge to liver transplantation (ALF and ACLF). Use of artificial ECLS has been studied in both ALF and ACLF. Artificial ECLS systems have been found to be safe and have demonstrated the following benefits: improvement of biochemistries, hemodynamic status, and hepatic encephalopathy. Despite this, only one prospective randomized controlled trial examining the use of high-volume plasma exchange has demonstrated improvement in transplant-free survival. Bioartificial (cell-based) ECLS systems build on the technology of artificial systems, incorporating living hepatocytes in a bioactive platform to further mimic endogenous hepatic detoxification and synthetic functions. Currently, no bioartificial system has been found to confer a mortality benefit; however, these platforms offer the greatest potential for future development.

Clinical effect of combined artificial extracorporeal liver support therapy for toxic hepatic failure

Objective: To investigate the clinical effect of plasma exchange (PE) versus double plasma molecular adsorption system combined with PE (DPMAS+PE) in the treatment of toxic hepatic failure. Methods: A total of 67 patients with toxic hepatic failure who were admitted during the same period of time were divided into PE group, DPMAS+ PE group, and control group. The 22 patients in the PE group were treated with PE alone, and the 24 patients in the DPMAS+PE group were given DPMAS combined with PE. The clinical out-come was compared between the three groups. Results: Both treatment groups had significantly higher clinical response rate and 24-week survival rate than the control group. After treatment, both treatment groups had significant reductions in the serum levels of total bilirubin (TBil) , direct bilirubin (DBil) , alanine aminotransfer-ase (ALT) , and aspartate aminotransferase (AST) , and the PE group had significant reductions in the albumin (Alb) level and activated partial thromboplastin time (APTT) (P<0.05) ; the DPMAS+PE group showed no sig-nificant changes in the Alb level and APTT (P>0.05). There were no significant differences in TBil, DBil, ALT, and AST between the two treatment groups after treatment (P>0.05). After treatment, the PE group had significantly higher Alb level and APTT than the DPMAS + PE group (P<0.05). Compared with the control group, both treatment groups had significant reductions in TBil, DBil, ALT and AST after treatment (P<0.05). Conclusion: The two artificial liver support techniques can significantly improve patients' liver function and in-crease their survival rate, and the combined artificial liver support technique can reduce the amount of plasma used.

One case of type II heparin-induced thrombocytopenia occurring in artificial extracorporeal liver support therapy

One case of type II heparin-induced thrombocytopenia occurring in artificial extracorporeal liver support therapy

MARS (Molecular Adsorbent Resirculation System) Treatment: A Single Sentre Report og 62 Cases

Background: MARS is an artificial extracorporeal liver support system allowing removal of albumin bound and water soluble toxins. MARS is expensive and efficacy of the treatment is not clear. The objective of this study was to report 30 days survival of patients treated with MARS. The experience of MARS treatment is currently registered into a prospective MARS registry. Methods: Sixty-two patients with different underlying cause of liver failure were treated with MARS in our hospital from 2005-2012 (49 adults and 13 children < 18 years). In addition to baseline biochemical parameters and demographics, we registered listing for liver transplantation, liver transplants performed as well as presentation, acute versus chronic. Survival data were compared with results from patients transplanted on the basis of acute liver failure (ALF) without MARS treatment in our unit during the period 2001-2010. Results: Median MELD-score was 36 (range 25-54) in the adult group and encephalopathy grade 4 (median) in the overall material. Time from onset of MARS treatment to transplantation was median 2 days (range 1-12) in the transplanted group (n=34). P-ammonia and bilirubin as well as creatinine and urea were significantly reduced after starting up MARS. 30 days overall survival in the adult group was 68 %, and in the pediatric group it was 77 %. Survival for transplanted (n=39) and for not transplanted (n=23) patients was 85 % and 39 %, respectively. Fourteen of all patients (22 %) were repeat transplantations. There was no increased mortality in these patients. No deaths were related to the MARS-treatment. 30 days survival for transplanted ALF was 96% (n=24) for patients not reciving MARS. However, in this group encephalopathy grade was 2 (median) and median MELD-score was 31 (range 14-40). Conclusion: MARS treatment is safe and effective in reducing known biochemical risk factors for death in patients with ALF. Thirteen children were treated with MARS and 30 days survival in these were not statistically inferior compared to adult patients.

Artificial extracorporeal liver support therapy in patients with severe liver failure

Severe liver failure is common and carries a high mortality risk in patients with both acute and acute-on-chronic liver failure. The failing liver constitutes a medical emergency, and in many cases liver transplantation is the only definite treatment. Extracorporeal liver support can be employed as a strategy for bridging to transplantation or recovery. This article focuses on options for artificial (nonbiological) extracorporeal treatment: single-pass albumin dialysis, fractionated plasma separation and adsorption (Prometheus®) and the molecular adsorbent recirculatory system. Their different principles, potential advantages and indications are discussed. Despite proven biochemical efficacy, there are little data regarding clinical end points. Thus far, molecular adsorbent recirculatory system therapy in acute and acute-on-chronic liver failure showed no survival benefit compared with standard medical therapy. Prometheus therapy showed reduced mortality in subgroups of higher severity of disease compared with standard medical therapy. Nevertheless, the value of extracorporeal liver support remains to be corroborated by further clinical studies that include the optimal timing, mode, intensity and duration of this treatment.

Preclinical characterization of primary porcine hepatocytes in a clinically relevant flat membrane bioreactor

Using primary porcine hepatocytes, artificial extracorporeal liver support (AEL) is a therapy that carries out the liver functions of liver failure patients until their own organs have been regenerated or until whole organ transplantation. Significant variation exists with regard to current bioreactor designs for AEL, and they may not reflect the in vivo architecture of the liver since each individual hepatocyte has its own direct contact with blood plasma for oxygen and nutrient supply and detoxification. The present study, based on our flat membrane bioreactor (FMB), aimed at in vivo liver architecture and to meet authentic clinical levels of human plasma exposure. Since many existing preclinical AELs are based on commercial culture medium with or without nonhuman serum, they may not authentically reflect the clinical situation in human patients, and little research has been done on human plasma exposure in in vitro culture-based bioreactors. To address this situation, herein we examined liver-specific functions such as albumin secretion, urea synthesis, glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), cell membrane stability by lactate dehydrogenase (LDH) test and ammonia clearance by using human plasma and serum-free medium in long-term culture of primary porcine hepatocytes to show the potential of our clinically relevant FMB. We observed that the organotypical double-gel (DG) culture is superior to conventional collagen-coated single-gel (SG) cultures. The performance of liver-specific functions by the FMB has long-term stability with intact cell morphology for up to 20 days under both plasma exposure and serum-free media. Our three focus points (long-term culture that correlates with the generation time of spontaneous regeneration, high-density culture, organotypical culture model using human plasma) may provide valuable clinical clues for AEL.

Usefulness and Safety of Extracorporeal Liver Support Therapy Using MARS® for Patients with Liver Failure: A Preliminary Report

The molecular adsorbent recirculating system (MARSR) is a form of artificial extracorporeal liver support and can be used for a bridge to spontaneous recovery of hepatic function or liver transplantation in patients with liver failure. This study evaluated the usefulness of MARSR in patients with liver failure. Between January 2004 and July 2007, 30 patients (21 males and 7 females; age 48.9+/-12.9 years) with acute or acute-on-chronic liver failure were managed using MARSR. We assessed laboratory data, the grade of hepatic encephalopathy, Child-Turcotte-Pugh class, and Model for End-Stage Liver Disease (MELD) score. The number of patients with acute liver failure and acute-on-chronic liver failure was 16 and 14, respectively. The mean cycle of MARSR in patients with liver failure was 2.2 sessions. After MARSR had been performed, serum total bilirubin, alanine aminotransferase (ALT), BUN, creatinine, ammonia level, daily urine output, and MELD score were improved (p<0.05). In contrast, MARSR failed to improve Child-Turcotte-Pugh score and the grade of hepatic encephalopathy. Liver transplantation was performed in 8 patients. Among them, 5 (62.5%) patients survived and 3 (37.5%) patients died. Twenty two patients underwent MARSR without liver transplantation and 4 (18.2%) of them survived. In patients with liver failure, MARSR improved the laboratory data and hepatic and renal function associated clinical characteristics. However, MARSR without liver transplantation did not improve survival. MARSR may be useful as a bridge therapy to liver transplantation in patients with liver failure.

Neutral Styrene Divinylbenzene Copolymers for Adsorption of Toxins in Liver Failure

In artificial extracorporeal liver support systems, albumin-bound toxins such as bilirubin, bile acids, or aromatic amino acids are removed by adsorption to polymer beads. To overcome the potential weaknesses of anion exchange polymers currently used in liver support, namely, binding of heparin and activation of coagulation, we prepared two series of neutral polystyrene divinylbenzene resins with average pore sizes of 5-6 and 8-9 nm, respectively. In in vitro experiments using human plasma spiked with bilirubin, cholic acid, tryptophan, and phenol, we found that only pores larger than 5-6 nm were accessible to strongly albumin-bound substances, such as bilirubin. On the other hand, less strongly albumin-bound substances, such as bile acids, were efficiently bound by polymers of the small pore size range due to a higher accessible surface area. None of the neutral resins bound significant amounts of heparin. To assess the influence of the polymers on activation of coagulation, generation of thrombin-antithrombin complexes (TAT) was measured at different citrate concentrations. While none of the neutral polymers induced TAT generation, TAT levels were significantly elevated after incubation of plasma with an anion exchange polymer that is in clinical use for extracorporeal liver support. Binding characteristics of the neutral resins for the natural anticoagulants protein C and antithrombin showed remarkable differences, with weak binding of antithrombin but strong removal of protein C, not only for the anion exchanger, but also for neutral polymers of the large pore size range. In conclusion, neutral polystyrene divinylbenzene polymers with a pore size larger than 5-6 nm are efficient adsorbents for albumin-bound toxins that do not induce generation of thrombin-antithrombin complexes.

Technology Insight: artificial extracorporeal liver support—how does Prometheus® compare with MARS®?

Artificial extracorporeal liver support or 'liver dialysis' has been used in patients with severe liver failure with increasing frequency since the Molecular Adsorbents Recirculating System (MARS), a variant of albumin dialysis, was introduced in 1999. Nevertheless, liver dialysis must still be thought of as experimental because its contribution to improved patient survival has not been proven in large randomized trials. Prometheus is a novel device for fractionated plasma separation via an albumin-permeable filter that was developed to improve removal of albumin-bound toxins. Initial studies have proven clinical use of Prometheus to be feasible and safe. Head-to-head comparisons of Prometheus and MARS have shown treatment with the former to be more efficient with respect to removal of most albumin-bound and water-solved markers. As controlled studies with clinical end points are lacking, it is not known whether the observed greater detoxification capacity of Prometheus will translate into clinical benefit; two small studies indicate that there might be a beneficial effect in hepatic encephalopathy and pruritus. In a recent randomized comparison of MARS and Prometheus, however, hemodynamic improvement was observed in response to MARS, but not Prometheus, treatment. A large randomized controlled trial investigating the effect of Prometheus on survival--the HELIOS study--has been initiated. First results are expected in 2008 and will be crucial to establishing a role for Prometheus in the field of extracorporeal liver support.

THIS ARTICLE HAS BEEN RETRACTED: An Australian Experience With the Molecular Adsorbents Recirculating System (MARS)

Abstract: The molecular adsorbents recirculating system (MARS) is a form of artificial extracorporeal liver support which has the potential to remove substantial quantities of albumin‐bound toxins postulated to contribute to the pathogenesis of liver cell damage, hemodynamic instability and multi‐organ failure in patients with acute liver failure and acute‐on‐chronic liver failure (AoCLF). We assessed the efficacy of MARS therapy in a cohort of patients with severe liver damage unresponsive to intensive medical therapy. MARS therapy was instituted late in the clinical course of six patients with severely impaired liver function refractory to intensive medical therapy, including four with AoCLF precipitated by sepsis and two with liver dysfunction due to sepsis in the absence of pre‐existing chronic liver disease. Outcome measures included markers of hemodynamic stability, renal function, serum bilirubin and bile acid levels, arterial ammonia levels, the arterial ketone body (acetoacetate/β‐hydroxybutyrate) ratio, hepatic encephalopathy grade and the plasma disappearance rate of indocyanine green. The rates of discharge from the intensive care unit and in‐hospital mortality were determined. Our findings suggest that MARS treatment might be associated with some clinical efficacy even in patients with advanced multi‐organ dysfunction occurring in the setting of severe liver damage and in whom treatment is instituted late in the clinical course. However, the overall survival rate (1/6; 17%) was poor. More data obtained from larger cohorts of patients enrolled in randomized controlled studies will be required in order to identify categories of liver failure patients who might benefit most from MARS treatment and to ascertain the most appropriate timing of intervention.